Impact of diabetes on stage I lung cancer treatment patterns and prognosis in older adults: A population-based cohort study.

Background: Diabetes is a common comorbidity in patients with early-stage non-small cell lung cancer (NSCLC), a growing population due to increased LC screening. However, it is unknown if diabetes is associated with less aggressive NSCLC treatment and worse NSCLC outcomes. This study aimed to investigate treatment patterns and outcomes of older patients with Stage I NSCLC and diabetes. Methods: Using national cancer registry data linked to Medicare, we identified patients ≥65 years old with Stage I NSCLC. Patients were categorized as having no diabetes, diabetes without severe complications (DM-c), or diabetes with ≥1 severe complication (DM + c). We used multinomial logistic regression to assess the association of diabetes and NSCLC treatment. The association of diabetes category with NSCLC and non-NSCLC survival was analyzed with Fine-Grey competing-risks regression. Results: In 25,358 patients (75% no diabetes, 12% DM-c and 13% had DM + c), adjusted analyses showed that DM-c and DM + c were associated with increased odds of receiving limited resection rather than lobectomy (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.07-1.37 and OR 1.42, 95% CI 1.26-1.59, respectively). Competing risk regression showed diabetes was associated with increased risk of non-NSCLC death (DM-c hazard ratio [HR] 1.16, 95% CI: 1.08-1.25, DM + c HR 1.49, 95% CI: 1.40-1.59), but not NSCLC-specific death. Conclusion: This study uncovers critical information on how diabetes is associated with less aggressive early-stage NSCLC care in older patients. This study also confirms that diabetes increases death from non-lung cancer causes and managing comorbidities is crucial to improving outcomes in older early-stage NSCLC survivors.

Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent.

Inflammation contributes to many chronic conditions. It is often associated with circulating pro-inflammatory cytokines and immune cells. GLP-1 levels correlate with disease severity. They are often elevated and can serve as markers of inflammation. Previous studies have shown that oxytocin, hCG, ghrelin, alpha-MSH and ACTH have receptor-mediated anti-inflammatory properties that can rescue cells from damage and death. These peptides have been studied well in the past century. In contrast, GLP-1 and its anti-inflammatory properties have been recognized only recently. GLP-1 has been proven to be a useful adjuvant therapy in type-2 diabetes mellitus, metabolic syndrome, and hyperglycemia. It also lowers HbA1C and protects cells of the cardiovascular and nervous systems by reducing inflammation and apoptosis. In this review we have explored the link between GLP-1, inflammation, and sepsis.

Subjective social status, race, and metabolic syndrome in women with breast cancer.

PURPOSE: To evaluate the association of subjective social status (SSS) with metabolic syndrome (MetS) severity and its potential contribution to racial health disparities in women with breast cancer. METHODS: Multicenter cross-sectional study (10 US hospitals) in women (n = 1206) with primary diagnosis of invasive breast cancer received during Mar/2013-Feb/2020. Participants, self-identified as non-Hispanic White or Black, underwent physical and laboratory examinations and survey questions assessing socioeconomic parameters, medical history, and behavioral risks. SSS was measured with the 10-rung MacArthur scale. MetS severity was measured with a validated Z-Score. Generalized linear mixed modeling was used to analyze the associations. Missing data were handled using multiple imputation. RESULTS: Average age was 58 years. On average, the SSS of Black women, given equivalent level of income and education, was lower than the SSS of White women: 6.6 (6.1-7.0) vs 7.7 (7.54-7.79) among college graduates and 6.8 (6.4-7.2) vs 7.6 (7.5-7.8) among women in the high-income category (> $75,000). In multivariable analysis, after controlling for age, income, education, diet, and physical activity, increasing SSS was associated with a decrease in MetS-Z score, - 0.10 (- 0.16 to - 0.04) per every 2 rung increase in the MacArthur scale. CONCLUSION: Black women with breast cancer rank their SSS lower than White women with breast cancer do at each level of income and education. As SSS is strongly associated with MetS severity these results identify potentially modifiable factors that contribute to racial disparities.

Unregulated LDL cholesterol uptake is detrimental to breast cancer cells.

Tumor uptake of exogenous cholesterol has been associated with the proliferation of various cancers. Previously, we and others have shown that hypercholesterolemia promotes tumor growth and silencing of the LDL receptor (LDLR) in high LDLR-expressing tumors reduces growth. To advance understanding of how LDL uptake promotes tumor growth, LDLR expression was amplified in breast cancer cell lines with endogenously low LDLR expression. Murine (Mvt1) and human (MDA-MB-468) breast cancer cell lines were transduced to overexpress human LDLR (LDLROE). Successful transduction was confirmed by RNA and protein analysis. Fluorescence-labeled LDL uptake was increased in both Mvt1 and MDA-MD-468 LDLROE cells. The expression of the cholesterol-metabolizing genes, ABCA1 and ABCG1, was increased, while HMGCR was decreased in the MDA-MB-468 LDLROE cells. In contrast, Mvt1 LDLROE cells showed no differences in Abca1 and Abcg1 expression and increased Hmgcr expression. Using a Seahorse analyzer, Mvt1 LDLROE cells showed increased respiration (ATP-linked and maximal) relative to controls, while no statistically significant changes in respiration in MDA-MB-468 LDLROE cells were observed. Growth of LDLROE cells was reduced in culture and in hypercholesterolemic mice by two-fold. However, the expression of proliferation-associated markers (Ki67, PCNA and BrdU-label incorporation) was not decreased in the Mvt1 LDLROE tumors and cells. Caspase-3 cleavage, which is associated with apoptosis, was increased in both the Mvt1 and MDA-MB-468 LDLROE cells relative to controls, with the Mvt1 LDLROE cells also showing decreased phosphorylation of p44/42MAPK. Taken together, our work suggests that while additional LDL can promote tumor growth, unregulated and prolonged LDL uptake is detrimental.

Hallmarks of cancer: The insulin-like growth factors perspective.

The identification of a series of attributes or hallmarks that are shared by virtually all cancer cells constitutes a true milestone in cancer research. The conceptualization of a catalogue of common genetic, molecular, biochemical and cellular events under a unifying Hallmarks of Cancer idea had a major impact in oncology. Furthermore, the fact that different types of cancer, ranging from pediatric tumors and leukemias to adult epithelial cancers, share a large number of fundamental traits reflects the universal nature of the biological events involved in oncogenesis. The dissection of a complex disease like cancer into a finite directory of hallmarks is of major basic and translational relevance. The role of insulin-like growth factor-1 (IGF1) as a progression/survival factor required for normal cell cycle transition has been firmly established. Similarly well characterized are the biochemical and cellular activities of IGF1 and IGF2 in the chain of events leading from a phenotypically normal cell to a diseased one harboring neoplastic traits, including growth factor independence, loss of cell-cell contact inhibition, chromosomal abnormalities, accumulation of mutations, activation of oncogenes, etc. The purpose of the present review is to provide an in-depth evaluation of the biology of IGF1 at the light of paradigms that emerge from analysis of cancer hallmarks. Given the fact that the IGF1 axis emerged in recent years as a promising therapeutic target, we believe that a careful exploration of this signaling system might be of critical importance on our ability to design and optimize cancer therapies.

Breast tumor IGF1R regulates cell adhesion and metastasis: alignment of mouse single cell and human breast cancer transcriptomics.

Introduction: The acquisition of a metastatic phenotype is the critical event that determines patient survival from breast cancer. Several receptor tyrosine kinases have functions both in promoting and inhibiting metastasis in breast tumors. Although the insulin-like growth factor 1 receptor (IGF1R) has been considered a target for inhibition in breast cancer, low levels of IGF1R expression are associated with worse overall patient survival. Methods: To determine how reduced IGF1R impacts tumor phenotype in human breast cancers, we used weighted gene co-expression network analysis (WGCNA) of Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) patient data to identify gene modules associated with low IGF1R expression. We then compared these modules to single cell gene expression analyses and phenotypes of mouse mammary tumors with reduced IGF1R signaling or expression in a tumor model of triple negative breast cancer. Results: WGCNA from METABRIC data revealed gene modules specific to cell cycle, adhesion, and immune cell signaling that were inversely correlated with IGF1R expression in human breast cancers. Integration of human patient data with single cell sequencing data from mouse tumors revealed similar pathways necessary for promoting metastasis in basal-like mammary tumors with reduced signaling or expression of IGF1R. Functional analyses revealed the basis for the enhanced metastatic phenotype including alterations in E- and P-cadherins. Discussion: Human breast and mouse mammary tumors with reduced IGF1R are associated with upregulation of several pathways necessary for promoting metastasis supporting the conclusion that IGF1R normally helps maintain a metastasis suppressive tumor microenvironment. We further found that reduced IGF1R signaling in tumor epithelial cells dysregulates cadherin expression resulting in reduced cell adhesion.

Insulin resistance and racial disparities in breast cancer prognosis: a multi-center cohort study.

The survival for breast cancer (BC) is improving but remains lower in Black women than White women. A number of factors potentially drive the racial differences in BC outcomes. The aim of our study was to determine if insulin resistance (defined as homeostatic model assessment for insulin resistance (HOMA-IR)), mediated part of the relationship between race and BC prognosis (defined by the improved Nottingham prognostic index (iNPI)). We performed a cross-sectional study, recruiting self-identified Black and White women with newly diagnosed primary invasive BC from 10 US hospitals between March 2013 and February 2020. Survey, anthropometric, laboratory, and tumor pathology data were gathered, and we compared the results between Black and White women. We calculated HOMA-IR as well as iNPI scores and examined the associations between HOMA-IR and iNPI. After exclusions, the final cohort was 1206: 911 (76%) White and 295 (24%) Black women. Metabolic syndrome and insulin resistance were more common in Black than White women. Black women had less lobular BC, three times more triple-negative BC, and BCs with higher stage and iNPI scores than White women (P < 0.001 for all comparisons). Fewer Black women had BC genetic testing performed. HOMA-IR mediated part of the association between race and iNPI, particularly in BCs that carried a good prognosis and were hormone receptor (HR)-positive. Higher HOMA-IR scores were associated with progesterone receptor-negative BC in White women but not Black women. Overall, our results suggest that HOMA-IR contributes to the racial disparities in BC outcomes, particularly for women with HR-positive BCs.

Racial differences in weight perception among Black and White women diagnosed with breast cancer.

PURPOSE: Black women are more likely than White women to have obesity, and obesity is associated with worse breast cancer prognosis. Weight perception, however, has not been studied as a potential mediator of obesity disparities in women with breast cancer. In this study, we sought to describe racial differences and the association of lifestyle factors with weight perception. METHODS: In this cross-sectional study design, Black and White women with a new primary breast cancer were surveyed about socio-demographics, weight perception, diet, and exercise habits. Height and weight were measured at enrollment. We classified women with a BMI ≥ 25 kg/m2 or waist circumference ≥ 88 cm who reported that they were "about the right weight" as under-perceivers. Chi-square and t tests were used to assess study variables (e.g., race, physical activity) associated with under-perception of weight. Logistic regression models were fit to evaluate for racial differences in under-perception while controlling for other covariates. RESULTS: Of 1,197 women with newly diagnosed breast cancer, the average age was 58 years, and 909 (75.9%) were White. Nine hundred eighteen (77%) had stage I cancer, 1,035 (87%) had estrogen receptor positive cancer, and 795 (66%) were privately insured at time of diagnosis. Seven hundred eighty-nine (66%) women had abdominal obesity (waist circumference ≥ 88 cm), while 366 (31%) women had a BMI ≥ 25 kg/m2. Overall, 24% of women were under-perceivers. Compared to White women, Black women with WC ≥ 88 cm more frequently under-perceived their weight (24% vs. 14% p < 0.0001) were more obese with BMI > 30 kg/m2 (51% vs. 23%, p < 0.0001) and had lower physical activity (22% vs. 77%, p < 0.0001). After controlling for age, education, and stage, Black women remained more likely to under-perceive their weight relative to White women for those with BMI ≥ 25 kg/m2 (OR: 2.64; 95% CI: 1.4-4.6) or waist circumference ≥ 88 cm (OR: 2.89; 95% CI: 1.8-4.5). With respect to lifestyle factors, among women with BMI ≥ 25 kg/m2, those who met physical activity guidelines were less likely to under-perceive their weight compared to those who did not meet physical activity guidelines (OR: 0.37; 95% CI: 0.2-0.6), regardless of race. CONCLUSIONS: We found racial differences in weight perception and identified social determinants and lifestyle factors such as lower education and physical inactivity that influenced under-perception of weight among newly diagnosed breast cancer patients. IMPLICATIONS FOR CANCER SURVIVORS: Since obesity is associated with worse breast cancer outcomes, identifying optimal modifiable factors to intervene upon to support weight management among breast cancer survivors is clinically important. Breast cancer patients' perceptions about their weight provide insight that may inform lifestyle behavior interventions to reduce obesity during survivorship care.

Oxytocin and Related Peptide Hormones: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis.

Sepsis is a potentially life-threatening systemic inflammatory syndrome characterized by dysregulated host immunological responses to infection. Uncontrolled immune cell activation and exponential elevation in circulating cytokines can lead to sepsis, septic shock, multiple organ dysfunction syndrome, and death. Sepsis is associated with high re-hospitalization and recovery may be incomplete, with long term sequelae including post-sepsis syndrome. Consequently, sepsis continues to be a leading cause of morbidity and mortality across the world. In our recent review of human chorionic gonadotropin (hCG), we noted that its major properties including promotion of fertility, parturition, and lactation were described over a century ago. By contrast, the anti-inflammatory properties of this hormone have been recognized only more recently. Vasopressin, a hormone best known for its anti-diuretic effect, also has anti-inflammatory actions. Surprisingly, vasopressin's close cousin, oxytocin, has broader and more potent anti-inflammatory effects than vasopressin and a larger number of pre-clinical studies supporting its potential role in limiting sepsis-associated organ damage. This review explores possible links between oxytocin and related octapeptide hormones and sepsis-related modulation of pro-inflammatory and anti-inflammatory activities.

TMEM176B Regulates AKT/mTOR Signaling and Tumor Growth in Triple-Negative Breast Cancer.

TMEM176B is a member of the membrane spanning 4-domains (MS4) family of transmembrane proteins, and a putative ion channel that is expressed in immune cells and certain cancers. We aimed to understand the role of TMEM176B in cancer cell signaling, gene expression, cell proliferation, and migration in vitro, as well as tumor growth in vivo. We generated breast cancer cell lines with overexpressed and silenced TMEM176B, and a therapeutic antibody targeting TMEM176B. Proliferation and migration assays were performed in vitro, and tumor growth was evaluated in vivo. We performed gene expression and Western blot analyses to identify the most differentially regulated genes and signaling pathways in cells with TMEM176B overexpression and silencing. Silencing TMEM176B or inhibiting it with a therapeutic antibody impaired cell proliferation, while overexpression increased proliferation in vitro. Syngeneic and xenograft tumor studies revealed the attenuated growth of tumors with TMEM176B gene silencing compared with controls. We found that the AKT/mTOR signaling pathway was activated or repressed in cells overexpressing or silenced for TMEM176B, respectively. Overall, our results suggest that TMEM176B expression in breast cancer cells regulates key signaling pathways and genes that contribute to cancer cell growth and progression, and is a potential target for therapeutic antibodies.

Human Chorionic Gonadotropin and Related Peptides: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis.

Sepsis continues to be a major cause of morbidity, mortality, and post-recovery disability in patients with a wide range of non-infectious and infectious inflammatory disorders, including COVID-19. The clinical onset of sepsis is often marked by the explosive release into the extracellular fluids of a multiplicity of host-derived cytokines and other pro-inflammatory hormone-like messengers from endogenous sources ("cytokine storm"). In patients with sepsis, therapies to counter the pro-inflammatory torrent, even when administered early, typically fall short. The major focus of our proposed essay is to promote pre-clinical studies with hCG (human chorionic gonadotropin) as a potential anti-inflammatory therapy for sepsis.

Regulation of low-density lipoprotein receptor expression in triple negative breast cancer by EGFR-MAPK signaling.

Expression of the low-density lipoprotein receptor (LDLR) has been shown to play a critical role in hypercholesterolemia-associated breast cancer growth and is associated with shorter recurrence-free survival in human breast cancer studies. We sought to identify how circulating LDL cholesterol and tumor LDLR might accelerate oncogenic processes by determining whether increased LDLR expression and cholesterol uptake are associated with the activation of the epidermal growth factor receptor (EGFR) signaling pathway in triple negative breast cancer (TNBC) cell lines. EGF stimulation of MDA-MB-468 (MDA468) cells activated p44/42MAPK (MAPK), increased expression of LDLR, and fluorescent LDL cholesterol uptake. However, stimulation of MDA-MB-231 (MDA231) cells with EGF did not lead to increased expression of LDLR despite inducing phosphorylation of EGFR. Inhibition of MAPK using UO126 in MDA231 cells reduced LDLR expression, and in MDA468 cells, UO126 impaired the LDLR increase in response to EGF. MDA468 cells exposed to the transcription inhibitor, Actinomycin, prior to treatment with EGF showed reduced degradation of LDLR mRNA compared to vehicle-treated cells. Our results suggest that the EGF-associated increase in LDLR protein expression is cell line-specific. The common pathway regulating LDLR expression was MAPK in both TNBC cell lines.

Insulin-like growth factors: Ligands, binding proteins, and receptors.

BACKGROUND: The insulin-like growth factor family of ligands (IGF-I, IGF-II, and insulin), receptors (IGF-IR, M6P/IGF-IIR, and insulin receptor [IR]), and IGF-binding proteins (IGFBP-1-6) play critical roles in normal human physiology and disease states. SCOPE OF REVIEW: Insulin and insulin receptors are the focus of other chapters in this series and will therefore not be discussed further. Here we review the basic components of the IGF system, their role in normal physiology and in critical pathology's. While this review concentrates on the role of IGFs in human physiology, animal models have been essential in providing understanding of the IGF system, and its regulation, and are briefly described. MAJOR CONCLUSIONS: IGF-I has effects via the circulation and locally within tissues to regulate cellular growth, differentiation, and survival, thereby controlling overall body growth. IGF-II levels are highest prenatally when it has important effects on growth. In adults, IGF-II plays important tissue-specific roles, including the maintenance of stem cell populations. Although the IGF-IR is closely related to the IR it has distinct physiological roles both on the cell surface and in the nucleus. The M6P/IGF-IIR, in contrast, is distinct and acts as a scavenger by mediating internalization and degradation of IGF-II. The IGFBPs bind IGF-I and IGF-II in the circulation to prolong their half-lives and modulate tissue access, thereby controlling IGF function. IGFBPs also have IGF ligand-independent cell effects.

Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score.

BACKGROUND: Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes. METHODS: A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores. RESULTS: Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m2, p < 0.0001), higher HOMA-IR score (2.4 vs. 1.4, p = 0.004), and more high-grade tumors (30% vs. 16%, p = 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p = 0.014). On subset analysis, this relationship was seen in White women (p = 0.005), but not in Black women (p = 0.55). CONCLUSION: In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.

Assessing the association of diabetes with lung cancer risk.

BACKGROUND: Diabetes is a well-established risk factor for many cancers, but its relationship with lung cancer incidence remains unclear. In this study, we aimed to assess if diabetes is independently associated with lung cancer risk and histology subtype among participants in a screening study. METHODS: In a retrospective cohort study using data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) study, we assessed the association of self-reported diabetes with lung cancer incidence using Poisson regression while adjusting for other established risk factors in the PLCOM2012, a validated lung cancer prediction model. The adjusted association of diabetes and lung cancer cell type was evaluated using nominal regression. Stratified analyses were also conducted according to sex, smoking history, and body mass index categories. RESULTS: Overall, 140,395 participants were included in our analysis. Diabetes was not significantly associated with lung cancer incidence [incidence rate ratio (IRR): 1.03, 95% confidence interval (CI): 0.91-1.17]. Similarly, stratified analyses also did not show significant associations between diabetes and lung cancer risk (all P values >0.05). We found no significant difference in the distribution of lung cancer histology in participants with vs. without diabetes (P=0.30). CONCLUSIONS: Diabetes was not an independent risk factor for lung cancer in a large cohort of PLCO participants. We did not observe differences in histology according to diabetes status. These results suggest that patients with diabetes do not need more aggressive lung cancer screening. Future research including more detailed metabolic parameters may further elucidate the relationship between metabolic disease and lung cancer risk.

Hyperinsulinaemia in cancer.

Elevated circulating insulin levels are frequently observed in the setting of obesity and early type 2 diabetes, as a result of insensitivity of metabolic tissues to the effects of insulin. Higher levels of circulating insulin have been associated with increased cancer risk and progression in epidemiology studies. Elevated circulating insulin is believed to be a major factor linking obesity, diabetes and cancer. With the development of targeted cancer therapies, insulin signalling has emerged as a mechanism of therapeutic resistance. Although metabolic tissues become insensitive to insulin in the setting of obesity, a number of mechanisms allow cancer cells to maintain their ability to respond to insulin. Significant progress has been made in the past decade in understanding the insulin receptor and its signalling pathways in cancer, and a number of lessons have been learnt from therapeutic failures. These discoveries have led to numerous clinical trials that have aimed to reduce the levels of circulating insulin and to abrogate insulin signalling in cancer cells. With the rising prevalence of obesity and diabetes worldwide, and the realization that hyperinsulinaemia may contribute to therapeutic failures, it is essential to understand how insulin and insulin receptor signalling promote cancer progression.

The midlife transition and the risk of cardiovascular disease and cancer Part I: magnitude and mechanisms.

Heart disease and cancer are the leading causes of death in the United States. In women, the clinical appearance of both entities-coronary heart disease and cancer (breast, endometrium, and ovary)-escalate during the decades of the midlife transition encompassing the menopause. In addition to the impact of aging, during the interval between the age of 40 and 65 years, the pathophysiologic components of metabolic syndrome also emerge and accelerate. These include visceral adiposity (measured as waist circumference), hypertension, diabetes, and dyslipidemia. Osteoporosis, osteoarthritis, sarcopenia, depression, and even cognitive decline and dementia appear, and most, if not all, are considered functionally related. Two clinical reports confirm the interaction linking the emergence of disease: endometrial cancer and metabolic syndrome. One describes the discovery of unsuspected endometrial cancer in a large series of elective hysterectomies performed in aged and metabolically susceptible populations. The other is from the Women's Health Initiative Observational Study, which found a positive interaction between endometrial cancer and metabolic syndrome regardless of the presence or absence of visceral adiposity. Both provide additional statistical support for the long-suspected causal interaction among the parallel but variable occurrence of these common entities-visceral obesity, heart disease, diabetes, cancer, and the prevalence of metabolic syndrome. Therefore, 2 critical clinical questions require analysis and answers: 1: Why do chronic diseases of adulthood-metabolic, cardiovascular, endocrine-and, in women, cancers of the breast and endometrium (tissues and tumors replete with estrogen receptors) emerge and their incidence trajectories accelerate during the postmenopausal period when little or no endogenous estradiol is available, and yet the therapeutic application of estrogen stimulates their appearance? 2: To what extent should identification of these etiologic driving forces require modification of the gynecologist's responsibilities in the care of our patients in the postreproductive decades of the female life cycle? Part l of this 2-part set of "expert reviews" defines the dimensions, gravity, and interactive synergy of each clinical challenge gynecologists face while caring for their midlife (primarily postmenopausal) patients. It describes the clinically identifiable, potentially treatable, pathogenic mechanisms driving these threats to quality of life and longevity. Part 2 (accepted, American Journal of Obstetrics & Gynecology) identifies 7 objectives of successful clinical care, offers "triage" prioritization targets, and provides feasible opportunities for insertion of primary preventive care initiatives. To implement these goals, a reprogrammed, repurposed office visit is described.

Insulin resistance contributes to racial disparities in breast cancer prognosis in US women.

BACKGROUND: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (ß = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R >  1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001). CONCLUSIONS: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.